Brain Parenchymal Fraction Research Articles

Automatic estimation of brain parenchymal fraction in patients with multple sclerosis: a comparison between synthetic MRI and an established automated brain segmentation software based on FSL

PurposeWe aimed to validate the estimation of the brain parenchymal fraction (BPF) in patients with multiple sclerosis (MS) using synthetic magnetic resonance imaging (SyMRI) by comparison with software tools of the FMRIB Software Library (FSL). In addition to a cross-sectional method comparison, longitudinal volume changes were assessed to further elucidate the suitability of SyMRI for quantification of disease-specific changes.MethodsMRI data from 216 patients with MS and 28 control participants were included for volume estimation by SyMRI and FSL-SIENAX. Moreover, longitudinal data from 35 patients with MS were used to compare registration-based percentage brain volume changes estimated using FSL-SIENA to difference-based calculations of volume changes using SyMRI.ResultsWe observed strong correlations of estimated brain volumes between the two methods. While SyMRI overestimated grey matter and BPF compared to FSL-SIENAX, indicating a systematic bias, there was excellent agreement according to intra-class correlation coefficients for grey matter and good agreement for BPF and white matter. Bland–Altman plots suggested that the inter-method differences in BPF were smaller in patients with brain atrophy compared to those without atrophy. Longitudinal analyses revealed a tendency for higher atrophy rates for SyMRI than for SIENA, but SyMRI had a robust correlation and a good agreement with SIENA.ConclusionIn summary, BPF based on data from SyMRI and FSL-SIENAX is not directly transferable because an overestimation and higher variability of SyMRI values were observed. However, the consistency and correlations between the two methods were satisfactory, and SyMRI was suitable to quantify disease-specific atrophy in MS.

Associations between homocysteine, tau, and neurodegenerative markers in apolipoprotein ε4 non‐carriers with clinical Alzheimer’s disease

AbstractBackgroundHomocysteine (Hcy) is an amino acid generated as a byproduct of methionine metabolism. It is a risk factor for vascular and neurodegenerative diseases. This study investigated relationships between plasma Hcy concentrations and neurodegenerative biomarkers in people clinically diagnosed with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.MethodParticipants were identified from the Ontario Neurodegenerative Disease Research Initiative. Brain parenchymal fraction (BPF) was quantified using T1‐ and T2‐weighted structural magnetic resonance imaging with an in‐house Semi‐Automated Brain Region Extraction and Lesion Explorer package. Plasma amyloid beta (Aβ) 42, Aβ40, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) were measured with Single molecule array (Simoa) assays. Linear regression analyses were used to test associations between Hcy and neuroimaging or plasma biomarkers, controlling for age, sex, hypertension, hyperlipidemia, diabetes, cholesterol, and vitamin B12. Analyses were stratified by apolipoprotein E (APOE) ε4 carrier status (non‐carriers: n = 64, mean age = 70.9 years, 41% female; carriers: n = 62, mean age = 71.2 years, 50% female).ResultIn APOE ε4 non‐carriers, Hcy was associated negatively with BPF (β = ‐0.233, p = 0.047, 95% CI [‐0.460, ‐0.003]), notably in temporal lobe regions in exploratory regional analyses. Hcy was also associated positively with plasma concentrations of NfL (β = 0.403, p = 0.007, 95% CI [0.117, 0.688]) and p‐tau181 (β = 0.357, p = 0.023, 95% CI [0.051, 0.663]) in APOE ε4 non‐carriers. Also, in APOE ε4 non‐carriers, Hcy was associated positively with Aβ40 (β = 0.367, p = 0.015, 95% CI [0.074, 0.660]) and Aβ42 (β = 0.305, p = 0.041, 95% CI [0.012, 0.598]), but not with the Aβ42/40 ratio (β = 0.155, p = 0.339, 95% CI [‐0.166, 0.476]). None of these associations were seen in APOE ε4 carriers.ConclusionIn non‐carriers of the APOE ε4 allele clinically diagnosed with AD or MCI, homocysteine was associated with Amyloid, tau and neurodegeneration. The specificity of these relationships to ε4 non‐carriers identifies a unique risk factor profile for AD that is independent of APOE ε4 status.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

Optical coherence tomography versus other biomarkers: Associations with physical and cognitive disability in multiple sclerosis

Background: Optical coherence tomography (OCT) is a biomarker of neuroaxonal loss in multiple sclerosis (MS). Objective: The objective was to assess the relative role of OCT, next to magnetic resonance imaging (MRI) and serum markers of disability in MS. Methods: A total of 100 patients and 52 controls underwent OCT to determine peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layers (GCIPL). Serum neurofilament light chain (sNfL), total lesion volume (TLV), and brain parenchymal fraction (BPF) were also assessed. The associations of OCT with disability were examined in linear regression models with correction for age, vision, and education. Results: In patients, pRNFL was associated with the Symbol Digit Modalities Test (SDMT; p = 0.030). In the multivariate analysis including sNfL and MRI measures, pRNFL (β = 0.19, p = 0.044) and TLV (β = −0.24, p = 0.023) were the only markers associated with the SDMT. pRNFL (p < 0.001) and GCIPL (p < 0.001) showed associations with the Expanded Disability Status Scale (EDSS). In the multivariate analysis, GCIPL showed the strongest association with the EDSS (β = −0.32, p < 0.001) followed by sNfL (β = 0.18, p = 0.024). Conclusion: The associations of OCT measures with cognitive and physical disability were independent of serum and brain MRI markers of neuroaxonal loss. OCT can be an important tool for stratification in MS, while longitudinal studies using combinations of biomarkers are warranted.

Pattern of Brain Parenchymal Damage Related to Cerebral Small Vessel Disease in Carriers of Rare NOTCH3 Variants.

Previous studies reported that carriers of rare NOTCH3 variants comprised more than 10% of the general population and are susceptible to a heavy overall burden of cerebral small vessel disease while the injury patterns remain uncovered. This study aimed to investigate the imaging features in relation to rare NOTCH3 variants and the interaction between cortical atrophy and white matter lesions from a longitudinal view, with respect to spatial and dynamic patterns. As part of a community-based cohort, we included participants with complete whole-exome sequencing and brain MRI in the baseline analysis. All participants were invited for a 5-year follow-up MRI, and those who did not complete the follow-up were excluded from the longitudinal analysis. NOTCH3 variants with minor allele frequency <1% in all 4 public population databases were defined as rare variants. We used general linear models to compare the volume of white matter hyperintensity (WMH) volume and brain parenchymal fraction between rare NOTCH3 variant carriers and noncarriers. In addition, we compared the WMH probability map and vertex-wise cortex maps at a voxel/vertex-wise level. A total of 1,054 participants were included in baseline analysis (13.56% carried rare NOTCH3 variants), among whom 661 had a follow-up brain MRI (13.76% carried rare NOTCH3 variants). Rare NOTCH3 variant carriers had a heavier white matter hyperintensity burden (1.65 vs 0.85 mL, p = 0.025) and had more extensive WMH distributed in the periventricular areas. We also found that rare NOTCH3 variant carriers were susceptible to worse cortical atrophy (β = -0.004, SE = 0.002, p = 0.057, adjusted for age and sex). Cortical atrophy of multiple regions in the frontal and parietal lobes was related to white matter hyperintensity progression. Individuals with rare NOTCH3 variants have a distinct pattern of brain parenchymal damage related to CSVD. Our findings uncover the important genetic predisposition in age-related cerebral small vessel disease in the general population.

Association of magnetic resonance imaging phenotypes and serum biomarker levels with treatment response and long-term disease outcomes in multiple sclerosis patients.

The aim was to evaluate whether magnetic resonance imaging (MRI) phenotypes defined by inflammation and neurodegeneration markers correlate with serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relapsing-remitting multiple sclerosis (RRMS) patients; and to explore the role of radiological phenotypes and biomarker levels on treatment response and long-term prognostic outcomes. Magnetic resonance imaging scans from 80 RRMS patients were classified at baseline of interferon-beta (IFNβ) treatment into radiological phenotypes defined by high and low inflammation and high and low neurodegeneration, based on the number of contrast-enhancing lesions, brain parenchymal fraction and the relative volume of non-enhancing black holes on T1-weighted images. Serum levels of NfL and GFAP were measured at baseline with single molecule array (Simoa) assays. MRI phenotypes and serum biomarker levels were investigated for their association with IFNβ response, and times to second-line therapies, secondary-progressive MS (SPMS) conversion and Expanded Disability Status Scale (EDSS) 6.0. Mean (SD) follow-up was 17 (2.9) years. Serum NfL levels and GFAP were higher in the high inflammation (p = 0.04) and high neurodegeneration phenotypes (p = 0.03), respectively. The high inflammation phenotype was associated with poor response to IFNβ treatment (p = 0.04) and with shorter time to second-line therapies (p = 0.04). In contrast, the high neurodegeneration phenotype was associated with shorter time to SPMS (p = 0.006) and a trend towards shorter time to EDSS 6.0 (p = 0.09). High serum NfL levels were associated with poor response to IFNβ treatment (p = 0.004). Magnetic resonance imaging phenotypes defined by inflammation and neurodegeneration correlate with serum biomarker levels, and both have prognostic implications in treatment response and long-term disease outcomes.

The CADA-MRIT: An MRI Inventory Tool for Evaluating Cerebral Lesions in CADASIL Across Cohorts.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent genetic cerebrovascular disease. The clinical aspects of the disease in relation to the various types of lesions on MRI vary widely not only within families but also between different cohorts reported worldwide. Many limitations prevent comparison of imaging data obtained with different scanners and sequences in different patient cohorts. We aimed to develop and validate a simple tool to inventory quickly the key MRI features in CADASIL to compare imaging data across different populations. The Inventory Tool (CADA-MRIT) was designed by consensus after repeated expert meetings. It consists of 11 imaging items to assess periventricular, deep, and superficial white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMB), centrum semiovale and basal ganglia dilated perivascular spaces (dPVS), superficial and deep atrophy, large infarcts, and macrobleeds. The reliability, clinical relevance, and time-effectiveness of CADA-MRIT were assessed using data from 3 independent patient cohorts. Imaging data from 671 patients with CADASIL (440 from France, 119 from Germany, and 112 from Taiwan) were analyzed. Their mean age was 53.4 ± 12.2 years, 54.5% were women, 56.2% had stroke, and 31.1% had migraine with aura. Any lacune was present in at least 70% of individuals, whereas CMB occurred in 83% of patients from the Asian cohort and in only 35% of European patients. CADA-MRIT scores obtained for WMH, CMB, and dPVS were comparable regardless of the scanner or sequence used (weighted κ > 0.60). Intrarater and interrater agreements were from good to very good (weighted κ > 0.60). Global WMH and atrophy scores correlated strongly with accurate volumetric quantification of WMH or brain parenchymal fraction (Pearson r > 0.60). Different imaging scores were significantly associated with the main clinical manifestations of the disease. The time for evaluating 1 patient was approximately 2-3 minutes. The CADA-MRIT is an easy-to-use tool for analyzing and comparing the most frequent MRI lesions of CADASIL across different populations. This instrument is reliable. It can be used with different imaging sequences or scanners. It also provides clinically relevant scores in a very short time for completion.

Brain Atrophy as an Outcome of Disease-Modifying Therapy for Remitting-Relapsing Multiple Sclerosis.

Currently, clinical trials of DMTs strive to determine their effect on neuroinflammation and neurodegeneration. We aimed to determine the impact of currently used DMTs on brain atrophy and disability in RRMS. The main goal of this review is to evaluate the neuroprotective potential of MS therapy and assess its impact on disability. We performed a systematic analysis of clinical trials that used brain atrophy as an outcome or performed post hoc analysis of volumetric MRI parameters to assess the neuroprotective potential of applied therapies. Trials between 2008 and 2019 that included published results of brain parenchymal fraction (BPF) change and brain volume loss (BVL) in the period from baseline to week 96 or longer were considered. Twelve from 146 clinical trials met the inclusion criteria and were incorporated into the analysis. DMTs that presented a large reduction in BVL also exhibited robust effects on clinical disability worsening, e.g., alemtuzumab with a 42% risk reduction in 6-month confirmed disability accumulation (p = 0.0084), ocrelizumab with a 40% risk reduction in 6-month confirmed disability progression (p = 0.003), and other DMTs (cladribine and teriflunomide) with moderate influence on brain atrophy were also associated with a marked impact on disability worsening. Dimethyl fumarate (DEFINE) and fingolimod (FREEDOMS I) initially exhibited significant effect on BVL; however, this effect was not confirmed in further clinical trials: CONFIRM and FREEDOMS II, respectively. Peg-IFN-β1a shows a modest effect on BVL and disability worsening. Our results show that BVL in one of the components of clinical disability worsening, together with other variables (lesion volume and annualized relapse rate). Standardization of atrophy measurement technique as well as harmonization of disability worsening and progression criteria in further clinical trials are of utmost importance as they enable a reliable comparison of neuroprotective potential of DMTs.

Brain MRI disease burden and sex differences in cognitive performance of patients with multiple sclerosis.

Although there is evidence that shows worse cognitive functioning in male patients with multiple sclerosis (MS), the role of brain pathology in this context is under-investigated. To investigate sex differences in cognitive performance of MS patients, in the context of brain pathology and disease burden. Brain MRI, neurological examination, neuropsychological assessment (Brief International Cognitive Assessment in MS-BICAMS, and Paced Auditory Verbal Learning Test-PASAT), and patient-reported outcome questionnaires were performed/administered in 1052 MS patients. Females had higher raw scores in the Symbol Digit Modalities Test (SDMT) (57.0 vs. 54.0; p < 0.001) and Categorical Verbal Learning Test (CVLT) (63.0 vs. 57.0; p < 0.001), but paradoxically, females evaluated their cognitive performance by MS Neuropsychological Questionnaire as being worse (16.6 vs 14.5, p = 0.004). Females had a trend for a weaker negative correlation between T2 lesion volume and SDMT ([Formula: see text] = -0.37 in females vs. -0.46 in men; interaction p = 0.038). On the other hand, women had a trend for a stronger correlation between Brain Parenchymal Fraction (BPF) and a visual memory test (Spearman's [Formula: see text] = 0.31 vs. 0.21; interaction p = 0.016). All these trends were not significant after correction for false discovery rate. Although, females consider their cognition as worse, males had at a group level slightly worse verbal memory and information processing speed. However, the sex differences in cognitive performance were smaller than the variability of scores within the same sex group. Brain MRI measures did not explain the sex differences in cognitive performance among MS patients.

CSF Markers of Oxidative Stress Are Associated with Brain Atrophy and Iron Accumulation in a 2-Year Longitudinal Cohort of Early MS.

In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels.

Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes.

Early risk-stratification in multiple sclerosis (MS) may impact treatment decisions. Current predictive models have identified that clinical and imaging characteristics of aggressive disease are associated with worse long-term outcomes. Serum biomarkers, neurofilament (sNfL) and glial fibrillary acidic protein (sGFAP), reflect subclinical disease activity through separate pathological processes and may contribute to predictive models of clinical and MRI outcomes. We conducted a retrospective analysis of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB study), where patients with multiple sclerosis are seen every 6 months and undergo Expanded Disability Status Scale (EDSS) assessment, have annual brain MRI scans where volumetric analysis is conducted to calculate T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and donate a yearly blood sample for subsequent analysis. We included patients with newly diagnosed relapsing-remitting MS and serum samples obtained at baseline visit and 1-year follow-up (both within 3 years of onset), and were assessed at 10-year follow-up. We measured sNfL and sGFAP by single molecule array at baseline visit and at 1-year follow-up. A predictive clinical model was developed using age, sex, Expanded Disability Status Scale (EDSS), pyramidal signs, relapse rate, and spinal cord lesions at first visit. The main outcome was odds of developing of secondary progressive (SP)MS at year 10. Secondary outcomes included 10-year EDSS, brain T2LV and BPF. We compared the goodness-of-fit of the predictive clinical model with and without sNfL and sGFAP at baseline and 1-year follow-up, for each outcome by area under the receiver operating characteristic curve (AUC) or R-squared. A total 144 patients with median MS onset at age 37.4 years (interquartile range: 29.4-45.4), 64% female, were included. SPMS developed in 25 (17.4%) patients. The AUC for the predictive clinical model without biomarker data was 0.73, which improved to 0.77 when both sNfL and sGFAP were included in the model (P=0.021). In this model, higher baseline sGFAP associated with developing SPMS (OR=3.3 [95%CI:1.1,10.6], P=0.04). Adding 1-year follow-up biomarker levels further improved the model fit (AUC=0.79) but this change was not statistically significant (P=0.15). Adding baseline biomarker data also improved the R-squared of clinical models for 10-year EDSS from 0.24 to 0.28 (P=0.032), while additional 1-year follow-up levels did not. Baseline sGFAP was associated with 10-year EDSS (ß=0.58 [95%CI:0.00,1.16], P=0.05). For MRI outcomes, baseline biomarker levels improved R-squared for T2LV from 0.12 to 0.27 (P<0.001), and BPF from 0.15 to 0.20 (P=0.042). Adding 1-year follow-up biomarker data further improved T2LV to 0.33 (P=0.0065) and BPF to 0.23 (P=0.048). Baseline sNfL was associated with T2LV (ß=0.34 [95%CI:0.21,0.48], P<0.001) and 1-year follow-up sNfL with BPF (ß=-2.53% [95%CI:-4.18,-0.89], P=0.003). Early biomarker levels modestly improve predictive models containing clinical and MRI variables. Worse clinical outcomes, SPMS and EDSS, are associated with higher sGFAP levels and worse MRI outcomes, T2LV and BPF, are associated with higher sNfL levels. Prospective study implementing these predictive models into clinical practice are needed to determine if early biomarker levels meaningfully impact clinical practice.

White matter hyperintensities in strategic tracts for cognitive impairment: A multicenter lesion‐symptom mapping study in 3525 memory clinic patients

AbstractBackgroundWhite matter hyperintensities (WMH) due to small vessel disease (SVD) are associated with dementia risk. Previous studies suggest that the cognitive impact of WMH depends on location. However, these studies were potentially limited by moderate brain lesion coverage. We aimed to identify strategic WMH locations for cognitive impairment in memory clinic patients by performing a large‐scaled multicenter study providing unprecedented lesion coverage.MethodIndividual patient neuropsychological and MRI data from eleven memory clinic cohorts were harmonized. Voxel based lesion symptom mapping‐ (VLSM) and region of interest (ROI) based analyses were performed to identify strategic WMH locations for four cognitive domains (attention and executive functioning, information processing speed, verbal memory, and language). A strategic WMH score was calculated based on quartiles of WMH volumes in the strategic white matter tracts and was related to cognition using Lasso regression, accounting for multicollinearity, and multivariable linear mixed models.ResultThe combined sample consisted of 3525 patients (age: 71.6 ± 9.0 years; 49.9% female) (Table 1). The WMH prevalence maps are shown in Figure 1. In the merged study sample, 63.0% of the supratentorial white matter was affected by WMH in ≥5 patients and could be included in the VLSM analysis. In the VLSM analysis, statistically significant voxels were found for each of the four cognitive domains, after correction for total WMH volume and multiple testing. These voxels were mostly located in the left and right anterior thalamic radiation and the forceps major. Independent ROI based analysis confirmed these strategic tracts and additionally identified the left inferior fronto‐occipital fasciculus as significant tract (Table 2). The strategic WMH score was significantly associated with lower performance on attention &amp; executive functioning (B‐0.146; p&lt;0.001), information processing speed (B‐0.090, p = 0.023), language (B‐0.124, p = 0.003), and verbal memory (B‐0.128, p&lt;0.001), independent of total WMH volume, age, sex, education, brain parenchymal fraction, and study site.ConclusionThis large multicenter study provides strong evidence that the cognitive impact of WMH in memory clinic patients depends on location and identified four significant white matter tracts. With further refinement, WMH location might become a useful diagnostic biomarker for SVD‐related cognitive impairment.

Early miR-320b and miR-25-3p miRNA levels correlate with multiple sclerosis severity at 10 years: a cohort study

BackgroundMultiple sclerosis (MS) is a chronic demyelinating autoimmune disorder which may cause long-term disability. MicroRNA (miRNA) are stable, non-coding molecules that have been identified in our Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB)-cohort, as well as other international cohorts, as potential disease biomarkers in MS. However, few studies have evaluated the association of miRNA expression early in the MS disease course with long-term outcomes. Therefore, we aimed to evaluate the potential role of three candidate serum miRNAs previously correlated with MS disability in patients with MS, miR-320b, miR-25-3p and miRNA 486-5p, as early biomarkers of MS disability at 10-year follow-up.Main bodyWe included 144 patients with serum obtained within three years of MS onset. miRNA expression was measured by RNA extraction followed by RT-PCR. Demographic, clinical, brain MRI and other biomarkers were collected. The primary outcome was the association between early miRNA expression and retaining benign MS, defined as EDSS ≤ 2 at 10-year follow-up. Among the 144 patients, 104 were benign and 40 were not benign at 10-year follow-up. 89 (62%) were women, with mean age at onset 37.7 (SD: 9.6) years. Patients who retained benign MS had lower values of miR-25-3p (p = 0.047) and higher miR-320b (p = 0.025) values. Development of SPMS was associated with higher miR-320b (p = 0.002) levels. Brain parenchymal fraction at year 10 was negatively correlated with miR-25-3p (p = 0.0004) and positively correlated with miR-320b (p = 0.006). No association was found between miR-486-5p and any outcome, and 10-year T2-lesion volume was not associated with any miRNA.ConclusionsOur results show that miR-320b and miR-25-3p expression are early biomarkers associated with MS severity and brain atrophy. This study provides class III evidence of that miR-320b and miR-25-3p are associated with long-term MS disability which may be a potential tool to risk-stratify patients with MS for early treatment decisions.

Functional assessment of the dural lymphatic vessels using dynamic contrast MRI in multiple sclerosis.

The discovery of glymphatic function in the human brain has generated interest in waste clearance mechanisms in neurological disorders such as multiple sclerosis (MS). However, noninvasive in vivo functional assessment is currently lacking. This work studies the feasibility of a novel intravenous dynamic contrast MRI method to assess the dural lymphatics, a purported pathway contributing to glymphatic clearance. This prospective study included 20 patients with MS (17 women; age=46.4 [27, 65] years; disease duration=13.6 [2.1, 38.0] years, expanded disability status score (EDSS)=2.0 [0, 6.5]). Patients were scanned on a 3.0T MRI system using intravenous contrast-enhanced fluid-attenuated inversion recovery MRI. Signal in the dural lymphatic vessel along the superior sagittal sinus was measured to calculate peak enhancement, time to maximum enhancement, wash-in and washout slopes, and the area under the time-intensity curve (AUC). Correlation analysis was performed to examine the relationship between the lymphatic dynamic parameters and the demographic and clinical characteristics, including the lesion load and the brain parenchymal fraction (BPF). Contrast enhancement was detected in the dural lymphatics in most patients 2-3min after contrast administration. BPF had a significant correlation with AUC (p<.03), peak enhancement (p<.01), and wash-in slope (p=.01). Lymphatic dynamic parameters did not correlate with age, BMI, disease duration, EDSS, or lesion load. Moderate trends were observed for correlation between patient age and AUC (p=.062), BMI and peak enhancement (p=.059), and BMI and AUC (p=.093). Intravenous dynamic contrast MRI of the dural lymphatics is feasible and may be useful in characterizing its hydrodynamics in neurological diseases.

Predicting MRI Changes in Patients with MS in the Absence of Acute Inflammation (P11-3.010)

Predicting MRI Changes in Patients with MS in the Absence of Acute Inflammation (P11-3.010)

Latinx with multiple sclerosis have greater disability and loss of deep and cortical gray matter (S31.003)

<h3>Objective:</h3> To characterize clinical and MRI features of Latinx with multiple sclerosis (MS). <h3>Background:</h3> MS affects an increasing number of Latinx patients. The clinical and radiological phenotype of Latinx MS is not well understood and may have biological or social underpinnings. <h3>Design/Methods:</h3> A retrospective cross-sectional study in the MS PATHS network was conducted with Latinx and White non-Latinx carrying a diagnosis of MS. Brain MRI conducted within 1 year of clinical visits were included in the MRI cohort. Clinical and quantitative MRI measures were extracted from MS PATHS including age- and education-adjusted processing speed tests. Comparisons between Latinx and White subjects were conducted using two-sample t-test and Wilcoxon rank-sum. Mixed effect models were used to examine clinical and MRI differences between Latinx and White subjects while adjusting for covariates including education, insurance, and employment. <h3>Results:</h3> A total of 660 Latinx and 9957 White subjects were identified with 388 Latinx and 5726 White subjects in the MRI cohort. Compared with White subjects, Latinx were younger (45.4 years [12.2] vs: 52.9 years [12.7], p &lt;0.001), had shorter disease duration (17.2 years [19.6] vs. 19.5 years [11.5], p &lt;0.001), and had lower processing speed z-score (−0.81 [1.3] vs. −0.40 [1.2], p &lt;0.001). Latinx had higher T2 lesion volume (8.0 ml [IQR 3.5–16] vs 6.5 ml [IQR 3.0–14.1], p = 0.009), and lower thalamic volume (12.8 ml [1.7] vs 13.3 ml [1.6], p &lt;0.001) compared to White subjects. Adjusted mixed models showed that Latinx subjects had lower processing speed, brain parenchymal fraction, thalamic volume, cortical volume, and deep gray matter volume (all p &lt;0.001) as well as slower walking speed (p=0.04), non-dominant manual dexterity (&lt;0.01), and higher PDDS (p=0.045). <h3>Conclusions:</h3> Latinx, despite being younger and having a shorter disease duration than Whites, had more physical disability, cognitive dysfunction, greater lesion burden, and loss of deep and cortical gray matter. <b>Disclosure:</b> Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech/Roche. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech/Roche. The institution of Dr. Ontaneda has received research support from NIH. The institution of Dr. Ontaneda has received research support from PCORI. The institution of Dr. Ontaneda has received research support from NMSS. The institution of Dr. Ontaneda has received research support from Genetech. Dr. McGinley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave. Dr. McGinley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. McGinley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. The institution of Dr. McGinley has received research support from Novartis. The institution of Dr. McGinley has received research support from Biogen. The institution of Dr. McGinley has received research support from Genentech. The institution of Dr. McGinley has received research support from NIH. Mr. Harvey has nothing to disclose. The institution of Dr. Fitzgerald has received research support from NIH. The institution of Dr. Fitzgerald has received research support from National MS Society. Dr. Mowry has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UpToDate. The institution of Dr. Mowry has received research support from Biogen. The institution of Dr. Mowry has received research support from Teva. The institution of Dr. Mowry has received research support from Genzyme. The institution of Dr. Mowry has received research support from Genentech. Dr. Cohen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Convelo. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mylan. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PSI. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage. The institution of Prof. Briggs has received research support from NIH. The institution of Prof. Briggs has received research support from Michael J. Fox Foundation.

The differential effects of APOE ɛ4 on cerebral volumetric structures in different lifespan in community-dwelling populations (P12-6.002)

<h3>Objective:</h3> In this study, we aimed to explore the age-related effect of APOE gene on brain volume. We hypothesized that APOE might have differential effects on brain volume in different age stages. <h3>Background:</h3> Apolipoprotein E (APOE) ɛ4 is closely related to Alzheimer’s disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. <h3>Design/Methods:</h3> Inhabitants in Shunyi District in Beijing aged 35 years and above and living independently were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. The detailed neuroimaging characteristics and brain volumes (global measures, cerebral lobes, subcortical nuclei and brainstem) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. <h3>Results:</h3> A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ɛ3/ɛ3 carriers accounted for 71.8%, ɛ2 allele 14.0%, and ɛ4 allele 14.2%. Compared with APOE ɛ3/ɛ3, a significant protective effect for APOE ɛ4 (+) on brain parenchyma fraction (β = 0.450, p = 0.048) was observed in subjects aged ≤60 years; in participants aged &gt;60 years, a negative effect for APOE ɛ4 (+) on hippocampus (β = 1.087, p = 0.021) was found. <h3>Conclusions:</h3> Our study reveals that APOE ɛ4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy. <b>Disclosure:</b> Dr. Tang has nothing to disclose. Dr. Su has nothing to disclose. Ding-Ding Zhang has nothing to disclose. Yi Dai has nothing to disclose. Ming Yao has nothing to disclose. Lixin Zhou has nothing to disclose. Liying Cui has nothing to disclose. Shuyang Zhang has nothing to disclose. Yi-Cheng Zhu has nothing to disclose. Jun Ni has nothing to disclose.

A 2-Stage Model of Heterogenous Treatment Effects for Brain Atrophy in MS Utilizing the MS PATHS Research Network (S27.001)

<h3>Objective:</h3> To extend 2-stage models of heterogenous treatment effect (HTE) to brain atrophy outcomes utilizing the MS PATHS research network. <h3>Background:</h3> 2-stage HTE models derived from real-world datasets have the potential to advance personalized medicine in MS. Brain atrophy provides an objective measure benefiting from highly standardized MRI capture. <h3>Design/Methods:</h3> Analyses included patients in MS PATHS who initiated DMT, had complete baseline data, and ≥1 year follow-up without switching DMT. DMT groups were based on efficacy: high (natalizumab, anti-CD20 monoclonal antibodies, alemtuzumab), moderate (fumarates, S1PR modulators, and cladribine) and low (teriflunomide, interferons, glatiramer acetate). Patients were split into training (70%) and test (30%) sets, stratified by group. In stage one, baseline brain parenchymal fraction (BPF) change risk models were derived by linear mixed effect models with baseline covariates as inputs; performance was assessed by predicted versus actual BPF change R-squared in the test set. In stage 2, propensity score (PS) weighting was performed, using multinomial logistic regression with baseline BPF change risk score as one of the covariates. Average treatment effect (ATE) and HTE were calculated with low-efficacy DMT as the reference. <h3>Results:</h3> Analyses included 594 high-, 184 moderate-, and 108 low-efficacy DMT-treated patients. Risk model performance R-squared=0.56. After PS adjustment, covariate SMDs were &lt;10%. In the ATE model, moderate- and high-efficacy groups had less brain atrophy than the low-efficacy group (p&lt;0.001). In the HTE model, BPF change was similar across groups for patients with low risk of brain atrophy. In patients with high risk of brain atrophy, high- and moderate-efficacy groups remained similar; the low-efficacy group had 2-fold worse BPF change. <h3>Conclusions:</h3> HTE models suggest individuals with low baseline risk of brain atrophy may achieve similar outcomes regardless of DMT efficacy choice. The worst relative outcomes occur when patients with high brain atrophy risk are treated with low-efficacy DMTs. <b>Disclosure:</b> Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech_GN41791. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol-Myers Squibb . Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Hersh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genzyme. The institution of Dr. Hersh has received research support from Biogen. The institution of Dr. Hersh has received research support from Novartis. The institution of Dr. Hersh has received research support from Genentech_GN41791. The institution of Dr. Hersh has received research support from PCORI. Dr. Sun has received personal compensation for serving as an employee of Biogen. Dr. Sun has stock in Biogen. Cynthia Grossman has received personal compensation for serving as an employee of Biogen. Cynthia Grossman has stock in Biogen . Dr. Shen has received personal compensation for serving as an employee of Biogen. Fabio Pellegrini has received personal compensation for serving as an employee of Biogen. Fabio Pellegrini has received stock or an ownership interest from Biogen. Nolan Campbell has received personal compensation for serving as an employee of Biogen. Nolan Campbell has stock in Biogen.

The Differential Effects of APOEɛ4 on Cerebral Volumetric Structures in Different Lifespan in Community-Dwelling Populations.

Apolipoprotein E (APOE) is closely related to Alzheimer's disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. We explored the age-related effect of APOE on brain volumes in a community-dwelling cohort. Inhabitants in Shunyi District in Beijing aged≥35 years were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. Neuroimaging small vessel disease characteristics and brain volumes (global measures, cerebral lobes, hippocampus, brainstem, and subcortical nuclei) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOEɛ3/ɛ3 carriers account for 71.8%, ɛ2 (+) 14.0%, and ɛ4 (+) 14.2%. Compared with APOEɛ3/ɛ3, a significant protective effect for APOEɛ4 (+) on brain parenchyma fraction (β = 0.450, p = 0.048) was observed in subjects aged≤60 years; in participants aged > 60 years, a negative effect for APOEɛ4 (+) on hippocampus (β = 1.087, p = 0.021) was found. Our study reveals that APOEɛ4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy.

Changes in Retinal Thickness and Brain Volume during 6.8-Year Escalating Therapy for Multiple Sclerosis

Background. Different disease-modifying therapies (DMT) for multiple sclerosis (MS) have disparate effects on disability outcomes. Sweden has a leading position globally in initiating high-efficacy DMT instead of escalating DMT from 1st-line to high-efficacy DMT. With optical coherence tomography (OCT), retinal changes can be measured at a few micrometer level. OCT has been increasingly applied in diagnosing MS and monitoring disease course and therapeutic effect. Objective. We investigate the effects of 1st-line versus high-efficacy DMT for MS on retinal and brain atrophy and on functional outcomes during 6.8 years of escalating DMT. Materials and Methods. In this prospective longitudinal observational study, 18 MS patients were followed up for 6.8 years. Twelve of the patients were untreated at baseline. All patients underwent 1st-line DMT for median duration of 2.4 years and then switched to high-efficacy DMT for a median duration of 2.9 years. Findings from neurological examinations, MRI, and OCT measures were registered 2-4 times per year. Results. Ganglion cell-inner plexiform layer (GCIPL) thickness was significantly reduced during 1st-line DMT (73.75 μm, p &lt; 0.01 ) compared to baseline (76.38 μm). During high-efficacy DMT, thickness reduction was slower (73.27 μm, p &lt; 0.05 ), and MRI contrast-loading lesions vanished ( p &lt; 0.01 ). However, brain parenchymal fraction (BPF) decreased during high-efficacy DMT compared to 1st-line DMT. Estimated models showed similar results. Conclusion. GCIPL decline was most profound during 1st-line DMT and diminished during high-efficacy DMT. MRI contrast lesions vanished during high-efficacy DMT. However, brain atrophy continued regardless of high-efficacy DMT.